Wnt proteins are conserved signalling molecules that have an essential role in regulating diverse processes during embryogenesis and adult tissue homoeostasis. Wnts are post-translationally modified by palmitoylation, which is essential for Wnt secretion and function. Intriguingly, the crystal structure of XWnt8 in complex with the extracellular domain of the Frizzled 8 cysteine-rich domain (Fzd8-CRD) revealed that Wnts use the fatty acid as a 'hotspot' residue to engage its receptor, which is a unique mode of receptor-ligand recognition. In addition, there are several lines of evidence suggesting that Wnts engage several signalling modulators and alternative receptors by means of fatty acids as a critical contact residue. In the present article, we review our current understanding of Wnt acylation and its functional role in Wnt signalling regulation.